Composition

This application claims priority to U.S. Provisional Application No. 60/982,790, filed Oct. 26, 2007, which is incorporated herein by reference in its entirety.

This invention relates to pharmaceutical compositions and methods of making them. More specifically the invention relates to pharmaceutical compositions containing licarbazepine acetate, especially eslicarbazepine acetate.

Eslicarbazepine acetate is a voltage-gated sodium channel (VGSC) blocker suitable for use as an anticonvulsant for example in treating epilepsy, affective disorders and neuropathic pain.

This molecule is structurally related to carbamazepine and oxcarbazepine, but has been specifically designed to reduce the production of toxic metabolites (such as epoxides) and to avoid enantiomeric impurity, and the unnecessary production of enantiomers or diastereoisomers of metabolites and conjugates, without losing pharmacological activity. It shares with carbamazepine and oxcarbazepine the dibenzazepine nucleus bearing the 5-carboxamide substitute but is differs at the 10,11-position. This molecular variation results in differences in metabolism, preventing the formation of toxic epoxide metabolites, such as carbamazepine-10,11 epoxide.

Broadly, the present invention relates to a pharmaceutical composition containing licarbazepine acetate, preferably eslicarbazepine acetate, in combination with at least one pharmaceutically acceptable excipient. The invention also relates to methods of making a pharmaceutical composition containing licarbazepine acetate, preferably eslicarbazepine acetate. The at least one excipient may include conventional excipients, such as one or more diluents/fillers, binders, disintegrants, glidants and lubricants. As used herein the term ‘composition’ is used interchangeably with the term ‘formulation’ and is intended to refer to the final oral dosage form such as a tablet or capsule.

According to one aspect of the invention, a pharmaceutical composition is provided wherein the composition comprises licarbazepine acetate, preferably eslicarbazepine acetate, in combination with a binder and a disintegrant, wherein the composition comprises granules of the licarbazepine acetate, and wherein at least part of the disintegrant is present in the granules (intragranular) and at least part of the disintegrant is extragranular.

According to another aspect, the present invention provides a pharmaceutical composition, in the form of an oral dosage form, comprising licarbazepine acetate, preferably eslicarbazepine acetate, wherein the composition does not contain any filler.

In accordance with another aspect of the invention, there is provided a pharmaceutical composition containing licarbazepine acetate, preferably eslicarbazepine acetate, in combination with at least one pharmaceutically acceptable excipient, wherein the composition does not include a wetting agent (i.e. there is no wetting agent at all in the composition).

The present invention results in a large increase in the bulk density: from about 0.28 g/mL in the API prior to granulation to, for example, around 0.6 g/mL in the mixture of drug and excipients (i.e. the preparation) prior to forming the final formulation, for example by compression to form a tablet or by capsule filling. Accordingly, another aspect of the present invention provides a pharmaceutical preparation, wherein the preparation comprises licarbazepine acetate, preferably eslicarbazepine acetate, in combination with a binder and a disintegrant, wherein the bulk density of the preparation is at least about 0.3 g/mL. In the preparation the licarbazepine acetate and part of the disintegrant are preferably present in granules whereas the remaining part of the disintegrant is extragranular. The preparation may further comprise extragranular lubricant. Other excipients may also be present as described in the Detailed Description below.

Preferably the preparation is formed into an oral dosage form, for example by compression to form a tablet.

Preferably the bulk density of the preparation is at least about 0.35 g/mL, more preferably about 0.40 g/mL, even more preferably about 0.45 g/mL, still more preferably about 0.50 g/mL, yet more preferably about 0.55 g/mL. Most preferably the bulk density of the preparation is at least about 0.60 g/mL.

The preparation may be used to form a pharmaceutical composition. In some embodiments, the pharmaceutical composition can be in the form of a solid oral dosage form, such as a tablet or capsule.

Another aspect of the present invention provides a capsule formulation, said formulation comprising a preparation as described above contained in a capsule. The present invention also provides a tablet formulation, said formulation comprising a preparation as described above compressed into a tablet form.

As a result of the improvement in bulk density the inventors have managed to reduce the size and apparent density of compressed formulations such as tablets. According to a another aspect of the invention, a compressed formulation is provided, preferably a tablet, wherein the formulation comprises licarbazepine acetate, preferably eslicarbazepine acetate, in combination with a binder and a disintegrant, wherein the formulation has an apparent density of about 0.5 to about 1.5 g/mL.